Create a translational medicine knowledge repository - Research downsizing, mergers and increased outsourcing have reduced the depth of in-house translational medicine expertise and institutional memory at many pharmaceutical and biotech companies: how will they avoid relearning old lessons?

Pharmaceutical industry consolidation and overall research downsizing threatens the ability of companies to benefit from their previous investments in translational research as key leaders with the most knowledge of the successful use of biomarkers and translational pharmacology models are laid off or accept their severance packages. Two recently published books may help to preserve this type of knowledge but much of this type of information is not in the public domain. Here we propose the creation of a translational medicine knowledge repository where companies can submit their translational research data and access similar data from other companies in a precompetitive environment. This searchable repository would become an invaluable resource for translational scientists and drug developers that could speed and reduce the cost of new drug development

False-Name Manipulation in Weighted Voting Games is Hard for Probabilistic Polynomial Time

False-name manipulation refers to the question of whether a player in a weighted voting game can increase her power by splitting into several players and distributing her weight among these false identities. Analogously to this splitting problem, the beneficial merging problem asks whether a coalition of players can increase their power in a weighted voting game by merging their weights. Aziz et al. [ABEP11] analyze the problem of whether merging or splitting players in weighted voting games is beneficial in terms of the Shapley-Shubik and the normalized Banzhaf index, and so do Rey and Rothe [RR10] for the probabilistic Banzhaf index. All these results provide merely NP-hardness lower bounds for these problems, leaving the question about their exact complexity open. For the Shapley--Shubik and the probabilistic Banzhaf index, we raise these lower bounds to hardness for PP, "probabilistic polynomial time", and provide matching upper bounds for beneficial merging and, whenever the number of false identities is fixed, also for beneficial splitting, thus resolving previous conjectures in the affirmative. It follows from our results that beneficial merging and splitting for these two power indices cannot be solved in NP, unless the polynomial hierarchy collapses, which is considered highly unlikely

Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A – C-Raf

Background: Recent advances in the treatment of melanoma that involve immunotherapy and B-Raf inhibition have revolutionised cancer care for this disease. However, an un-met clinical need remains in B-Raf inhibitor resistant patients where first-generation B-Raf inhibitors provide only short-term disease control. In these cases, B-Raf inhibition leads to paradoxical activation of the C-Raf – MEK – ERK signalling pathway, followed by metastasis. PDE8A has been shown to directly interact with and modulate the cAMP microdomain in the vicinity of C-Raf. This interaction promotes C-Raf activation by attenuating the PKA-mediated inhibitory phosphorylation of the kinase. Methods: We have used a novel cell-penetrating peptide agent (PPL-008) that inhibits the PDE8A – C-Raf complex in a human malignant MM415 melanoma cell line and MM415 melanoma xenograft mouse model to investigate ERK MAP kinase signalling. Results: We have demonstrated that the PDE8A – C-Raf complex disruptor PPL-008 increased inhibitory C-Raf-S259 phosphorylation and significantly reduced phospho-ERK signalling. We have also discovered that the ability of PPL-008 to dampen ERK signalling can be used to counter B-Raf inhibitor-driven paradoxical activation of phospho-ERK in MM415 cells treated with PLX4032 (Vemurafenib). PPL-008 treatment also significantly retarded the growth of these cells. When applied to a MM415 melanoma xenograft mouse model, PPL-008C penetrated tumour tissue and significantly reduced phospho-ERK signalling in that domain. Conclusion: Our data suggests that the PDE8A-C-Raf complex is a promising therapeutic treatment for B-Raf inhibitor resistant melanoma

Factorized Q-Learning for Large-Scale Multi-Agent Systems

Deep Q-learning has achieved significant success in single-agent decision making tasks. However, it is challenging to extend Q-learning to large-scale multi-agent scenarios, due to the explosion of action space resulting from the complex dynamics between the environment and the agents. In this paper, we propose to make the computation of multi-agent Q-learning tractable by treating the Q-function (w.r.t. state and joint-action) as a high-order high-dimensional tensor and then approximate it with factorized pairwise interactions. Furthermore, we utilize a composite deep neural network architecture for computing the factorized Q-function, share the model parameters among all the agents within the same group, and estimate the agents' optimal joint actions through a coordinate descent type algorithm. All these simplifications greatly reduce the model complexity and accelerate the learning process. Extensive experiments on two different multi-agent problems demonstrate the performance gain of our proposed approach in comparison with strong baselines, particularly when there are a large number of agents.Comment: 7 pages, 5 figures, DAI 201

Fundamental Solutions for the Klein-Gordon Equation in de Sitter Spacetime

In this article we construct the fundamental solutions for the Klein-Gordon equation in de Sitter spacetime. We use these fundamental solutions to represent solutions of the Cauchy problem and to prove $L^p-L^q$ estimates for the solutions of the equation with and without a source term

An exploration of ebook selection behavior in academic library collections

Academic libraries have offered ebooks for some time, however little is known about how readers interact with them while making relevance decisions. In this paper we seek to address that gap by analyzing ebook transaction logs for books in a university library

AAAS joins the Translational Medicine family

The AAAS has announced the launch of Science Translational Medicine. This is further and critical recognition of this discipline and we are deeply gratified that translational medicine has risen to the level of recognition by one of the world's most prestigious scientific organizations. We believe that Science Translational Medicine will provide another valuable venue for the rapid and broad dissemination of important articles in the field and contribute to enhancing the effectiveness of translational medicine overall

Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches

B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4−/− B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We also find that CXCR4 can contribute to T cell homing. Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized. In Peyer's patches, B cell entry is dependent on CXCR5 in addition to CCR7/CXCR4. CXCL12 (SDF1) is displayed broadly on HEVs, whereas CXCL13 (BLC) is found selectively on Peyer's patch follicular HEVs. These findings establish the principal chemokine and chemokine receptor requirements for B cell entry to lymph nodes and Peyer's patches

A log analysis study of 10 years of ebook consumption in academic library collections

Even though libraries have been offering eBooks for more than a decade, very little is known about eBook access and consumption in academic library collections. This paper addresses this gap with a log analysis study of eBook access at the library of the University of Waikato. This in-depth analysis covers a period spanning 10 years of eBook use at this university. We draw conclusions about the use of eBooks at this institution and compare the results with other published studies of eBook usage at tertiary institutes

Eau de Cleopatra: Mendesian perfume and Tell Timai

A combination of Classics, Egyptology, and experimental archaeology were utilized to recreate the (in)famous perfume used by Queen Cleopatra VII. Especially important was the use of classical sources and paleobotany to determine the identity of the Egyptian sacred oils such as camphor and balanos. Excavations at the site of Tell Timai revealed a perfumery that contributed to our ability to recreate the process of perfume manufacture. This ancient “Mendesian” perfume has since been recreated in the lab, exhibited at the Smithsonian, and worn again for the first time in millennia